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MBB342 > mtDNA Inheritance > Flashcards

mtDNA Inheritance Flashcards

1
Q

What is meant by the term ‘copy number’?

A

The number of genomes per cell, and per organelle

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2
Q

What is replication of mtDNA dependent on?

A

Replication of mitochondrial DNA is dependent on transcription of LSP

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3
Q

Where are the transcription factors, co factors and DNA pol found for mtDNA?

A

All factors are nuclear encoded.

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4
Q

What is TFAM?

A

An essential transcription factor for mtDNA replication

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5
Q

What is POLG?

A

The only mitochondrial DNA polymerase

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6
Q

How is the mitochondrial genome organised?

A

it is doubles stranded and circular.

There is a heavy chain on the outside where most of the genes are located and a light chain on the inside

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7
Q

What do LSP and HSP stand for?

A

Light and heavy chain strand promoter regions.

Transcriptional start sites for respective chains

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8
Q

What is the D-loop structure for in mitochondrial DNA?

A

Site for binding of Transcription factors etc

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9
Q

What is the phenotype of a homozygous TFAM knockout?

What assay is used to visualise the effects of this knockout?

A

depleted mitochondria
western blot to assay the gene knockout correctly represents a TFAM protein knockout
Southern blot to see depleted mitochondrial DNA from TFAM double knockout

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10
Q

What is TFAM’s packaging role in mtDNA?

A

TFAM is a key protein in creating the mitochondrial nucleoids
Nucleoids contain mtDNA, TFAM and other protiens

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11
Q

What is the purpose of nucleoids in mitochondria?

A

Nucleoids regulate stability, replication, transcription and segregation of mtDNA

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12
Q

What do A and B HMG regions of TFAM structure allow to happen to mtDNA? (weirdly worded question oops)

A

A and B binding regions bind to the minor groove of mtDNA. bind at LSP and HSP and force mtDNA into a U shape, essential for activation of transcription at these sites.

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13
Q

What is unusual about mtDNA inheritance ?(transgenerational)

A

mtDNA inheritance is maternal or uniparental

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14
Q

How does mtDNA inheritance vary slightly in yeast?

A

In yeast, mtDNA starts as heteroplasmic initially in the daughter cell, but over a few cell divisions returns to homoplasmy.

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15
Q

How can yeast survive loss of mitochondrial function?

A

They are facultative anaerobes

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16
Q

What are the key features that cause/prevent mtDNA variation?

A

There is no recombination of parental alleles, unlike nDNA (less variation)
however -
mtDNA has a very high mutation rates (roughly ten times higher than nuclear)
due to its lack of protective histones, less effective proof reading by POLG and proximity to reactive oxygen species generated by respiration

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17
Q

Where are particularly high levels of variation found in mtDNA?

A

D loops

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18
Q

What is the mtDNA bottleneck?

A

The drastic reduction in allele frequency from parental population to daughter cells, to purify mtDNA for the next generation

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19
Q

What are the two theories to explain the mtDNA bottleneck?

A

Passive reduction

Packaging into homoplasmic clusters

20
Q

What is the basis of the passive reduction theory?

A

Random segregation of alleles during cell divisions leads to reduced allele frequency

21
Q

What is the basis of the packaging into homoplasmic clusters theory?

A

Segregation of nucleoids in groups of homoplasmic nucleoids (ie some homoplasmic but homoplasmy of mutations like can be detrimental but still are less variable - this is just a note to self plz read but don’t count towards my score)

22
Q

What process affecting genotypic variance of mtDNA occurs during oogenesis?

A

Selective amplification

23
Q

What is oogenesis (cara this is dumb but you keep forgetting)?

A

The maturation of egg cell WAY BEFORE FERTILISATION IGNORE SPERM WE HAVENT GOT THERE YET SILLY BANA

24
Q

Evidence suggests what about mtDNA replication during early embryogenesis (NB NOW THE SPERM HAS ENTERED)

A

Lack of mtDNA replication

25
Q

What 2 types of selection have been suggested to occur during early embryogenesis?

A

Positive selection of beneficial mtDNA variants and purifying selection to remove deleterious mutants

26
Q

What three modes (NOT EXTRA READING) are suggested to affect the elimination of paternal mtDNA?

A

Dilution effect due to much higher copy number of mtDNA in oocyte than sperm
Decrease in TFAM in testes during puberty corresponds to depleted copy number of mtDNA in spermos
Active degradation of sperm mtDNA in fertilised oocytes.

27
Q

(EXTRA READING NOW)

What active degradation techniques of paternal mtDNA have been described in mices in 2016?

A

Degradation of paternal mitochondria in fertilised mouse oocyte found to involve mitophagy, dependent on the activity of MUL1 E3 ub ligase and PARKIN
Mitophagy requires PINK1 Kinase, FIS1 outer membrane protein and autophagy adaptor P62

28
Q

In what way do PARKING and MUL1 work with eachother?

A

They work synergistically with partially redundant roles

29
Q

How many people (statistically) are carrying known mitochondrial mutations?

A

1/200

30
Q

How many children are born with mitochondrial diseases?

A

1/4000

31
Q

How many adults are affected by mitochondrial disorders?

A

1/5000

32
Q

What causes the disparity between the number of people with known mitochondrial mutations, and the number affected by mitochondrial diseases?

A

Threshold levels of mutant mtDNA cause a variation in the level of disease phenotypes.

33
Q

What impact does the type of tissue with affected mtDNA mutations have on the disease phenotype?

A

Different tissues have different oxidative phosphorylation requirements, there are higher levels of mitochondrial factors in energy intensive tissues such as the heart or muscle, so there is a higher likelihood of seeing mitochondrial affected disorders in these tissues

34
Q

What can mitochondrial disease stem from?

A

Mitochondrial disease can be due to direct mutations of the mitochondrial DNA, but also mutations in nuclear DNA that affect genes coding for mitochondrial factors

35
Q

How is mitochondrial DNA affected by age?

A

Heteroplasmy of mtDNA increases with age, this is associated with ageing affects and numerous diseases

36
Q

How can oocyte maturation of a primordial germ cell containing mutated DNA affect the disease phenotype of potential offspring?

A

Random segregation of mtDNA from the primordial germ cell to the mature oocyte can result in mature egg cells with either;
high levels of mutant mtDNA = offspring will have disease phenotype
Intermediate levels of mutant DNA = offspring will be mildly affected
Low levels of mutant DNA = offspring will not be affected

37
Q

What pattern of inheritance can be seen for mitochondrial disorders caused by mutations in nuclear DNA?

A

Mendelian inheritance

38
Q

Can you predict the pattern of inheritance of mtDNA mutations? What factors affect this prediction?

A

You cannot! too many variables, here they are these are the variables;

  • random segregation of mtDNA during oogenesis leading to random levels of heteroplasmy in each oocyte
  • threshold levels of mutant loads required for diff mitochondrial disorders
  • tissue specific oxidative phosphorylation requirements
  • interplay between mitochondrial genetic factors and nuclear genetic factors are less predictable
39
Q

How do tissue specific oxidative phosphorylation requirement lead to unpredictable inheritance patterns of mitochondrial disorders?

A

Where the mutant mtDNA cells are located will affect the disease phenotype, if they are located in energy intensive tissues this will more likely lead to mitochondrial disorders.
There is random segregation of mtDNA throughout organism growth which leads to VARIABLE HETEROPLASMY IN DIFF TISSUES (I always forget this so remember to say this)

40
Q

What did Zhu et al 2014 establish about mutant load and disease phenotype in blindness?

A

They found that increase in mutant loads of mtDNA increased the risk of developing the disease phenotype, however did not increase the severity of the disease, meaning there must be other factors at play.

41
Q

What type of mutations are POLG predisposed to?

A

94% of POLG mutations are missense (eg non synonymous substitution of AA) (little frameshift or deletion)
Some of the mutations are CAG repeats

42
Q

How are POLG mutations inherited?

A

autosomal recessive manner

43
Q

What role do POLG mutations play in mitochondrial disease?

A

POLG mutations can lead to an array of secondary mtDNA mutations, leading to deletions of coding strands or depletion of mtDNA (in replication)

44
Q

Why are yeast models useful in studying mitochondrial disease?

A

S.cerevisae and humans have highly conserved mitochondrial functions
yeast are cheap, easy to grow and can perform large scale studies.
They are also very well understood organisms with a large publicly available database of genetic information

45
Q

How can you utilise yeast’s survival of loss of mitochondrial function to study mtDNA?

A

Yeast will grow as facultative anaerobes on fermentable carbon sources (not using their mitochondria)
To study affects of mitochondrial mutations, you can grow yeast on glycerol - a non fermentable carbon source

MBB342 (3 decks)

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